The importance of opsonic alpha 2 SB glycoprotein as a determinant of macrophage phagocytic activity during tumor growth was investigated. In addition, the opsonic protein from rat and human serum was isolated and characterized and an immunoassay for its quantification was developed. We also tested the hypothesis that opsonin therapy during surgery could circumvent macrophage phagocytic depression. The opsonic protein has a molecular weight of approximately 450,000 daltons and is identical to cold-insoluble globulin or so called plasma fibronectin. Both proteins have identical migrations in both the native and reduced states; demonstrate lines of identity with monospecific antiserum against either the opsonic glycoprotein or cold-insoluble globulin; and have a similar amino acid composition. With electroimmunoassay, its level in both animals and humans is approximately 300-500 micron g/ml and falls significantly following operative stress. Intravenous administration of the opsonic protein will prevent phagocytic depression after surgery and the intralesional administration of the opsonic protein at the site of tumor cell transplantation will impair growth. A parallel clinical study evaluating the influence of BCG therapy on the circulating levels of this opsonic protein is in progress. These collective studies suggest that the antitumor defense mechanism as mediated through the macrophage system may be, in part, determined by the serum level of this protein which stimulates macrophage recognition of malignant cells. Major operative intervention may depress the antitumor defense capacity of the macrophage system.